Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths in American women. Metastatic disease including metastatic breast cancer unfortunately remains incurable. One reason is due to the inability to develop specific therapies for specific cancer subsets.

The use of modern genomic techniques has significantly enhanced our recent understanding of breast cancer biology. Five distinct breast cancer subsets have been recognized, one of which is basal-like breast cancer. Basal-like breast cancer is typically estrogen receptor (ER) negative, progesterone receptor (PR) negative and human epidermal growth factor receptor 2 (HER-2-Neu) negative. This is referred to as triple negative breast cancer or TBNC. TBNC represents a significant proportion of breast cancer patients (10-20%) and has a poor prognosis with no targeted approach to therapy as of yet.

Tigatuzumab is a humanized monoclonal antibody targeting a death receptor on the breast cancer cells. Previous studies have shown that combining antibodies with selected chemotherapy agents have induced tumor cell death. The hypothesis of this study is to use tigatuzumab and combine it with Abraxane to serve as a targeting agent in metastatic TBNC patients.

Further study details as provided by University of Alabama at Birmingham:

Primary Outcome Measures:

Objective response rate [ Time Frame: Interim analysis will be conducted after 11 patients have been accrued and completed in each arm. Final analysis will be at the conclusion of the study: about 2 years. ] [ Designated as safety issue: No ]

The primary endpoint of this trial is the objective response rate as measured by complete responses and partial responses for the combination of tigatuzumab and Abraxane or Abraxane alone in patients with metastatic triple negative breast cancer. This information will be used to generate hypotheses for further trials.

Secondary Outcome Measures:

Characterization of the safety profile and treatment tolerance [ Time Frame: An interim safety analysis will be done for the first 6 patients enrolled in the combination group. The study will be on hold at that time. Final toxicity and safety evaluation will be at the conclusion of the study: about 2 years. ] [ Designated as safety issue: Yes ]

The trial will allow for further characterization of the safety profile and treatment tolerance of tigatuzumab in combination with Abraxane.

Correlate circulating tumor cells with the objective response rate and the progression free survival observed in both groups. [ Time Frame: ~2 years ] [ Designated as safety issue: No ]

Correlate serial measures of circulating tumor cells with the objective response rate and progression free survival observed in both groups. Changes will also be observed in apoptosis marker staining in the circulating tumor cells and correlation will be made to the corresponding serum levels.

Characterize the immune response to tigatuzumab [ Time Frame: ~2 years ] [ Designated as safety issue: No ]

Characterize patient immune response to tigatuzumab when administered in combination with Abraxane.

Evaluate the pharmacokinetics of the combined drugs (UAB only) [ Time Frame: ~2 years ] [ Designated as safety issue: No ]

Determine the pharmacokinetics of tigatuzumab and Abraxane when given in combination. (This will be done only at UAB.)

Patients will receive Abraxane at 100 mg/m2 X 3 doses on Days 1, 8, and 15 at 28-day intervals in combination with tigatuzumab to be administered as a 10 mg/kg loading dose followed by 5 mg/kg for the first cycle and then every other week on Days 1 and 15 for subsequent cycles. Patients will be evaluated for response every 8 weeks. Patients with disease progression will be taken off the study.

Drug: Tigatuzumab

Tigatuzumab will be administered as a loading dose of 10 mg/kg on Day 1, then 5 mg/kg on Day 15 and then every other week on Days 1 and 15 of subsequent cycles. It will be given as an IV infusion over 60 minutes or less. No dose reductions will be allowed. Tigatuzumab will be administered in combination with the Abraxane according to the intervention described for it.

Other Name: Tigatuzumab, CS-1008

Experimental: Abraxane alone

Patients will receive Abraxane at 100 mg/m2 weekly X 3 doses on Days 1, 8, and 15 at 28-day intervals. Treatment may continue without interruption in patients with complete response (CR), partial response (PR), or stable disease (SD) until there is progression of the disease or unacceptable toxicity. Patients will have the option to crossover to the combination arm based upon the pre-clinical data.

Drug: Abraxane

100 mg/m2 weekly X 3 doses (Days 1, 8, 15) at 28-day intervals until disease progression or unacceptable toxicity. Abraxane will be administered on an outpatient basis by an IV infusion over 30 minutes. Patients will be evaluated for response every 2 cycles (every 8 weeks).

Other Name: Abraxane, also ABI-007

Detailed Description:

The study is an open-label randomized, multi-institutional, phase II clinical trial of Abraxane in combination with tigatuzumab or Abraxane as a single agent in patients with TNBC. Randomization (2:1) will be made from these two categories: TBNC patients with no prior chemotherapy for metastatic disease or TBNC patients with prior taxane (except Abraxane) therapy for metastatic disease. Patients randomized to Abraxane alone may be allowed to cross over to the combination of Abraxane + tigatuzumab if there is disease progression.

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Patients must have pathologically documented Stage IV breast cancer. If blocks (paraffin-embedded tissue) from original diagnosis are available, they will be obtained to confirm the diagnosis and for correlative studies. Fifteen slides can be obtained from the block if the block is not available to be sent or released.

Tumor must be HER-2-neu negative (defined as 0 or 1+ staining by immunohistochemistry or gene amplification ratio less than or equal to 2.0, by fluorescent in situ hybridization - FISH), estrogen and progesterone receptors negative (<10%).

Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded)

Biopsy of a metastatic lesion is not required for protocol entry but all patients with reasonably accessible lesions (chest wall, breast, skin, subcutaneous, superficial lymph nodes, bones and liver metastases) must agree to biopsy.

Biopsies may be done with local anesthesia or intravenous conscious sedation, according to standard institutional guidelines.

If a biopsy requires general anesthesia, then it is only allowed if acquisition of tissue is necessary for clinical reasons and excess tissue that would otherwise have been discarded is then used for research purposes. If a biopsy requires general anesthesia, then a biopsy of that site for research purposes only, without a coexisting clinical indication is not allowed on this protocol.

Patients with reasonably accessible lesions as described above, who will not agree with the biopsy, will not be enrolled in the trial.

Patients with NO reasonably accessible lesions as described above can be enrolled in the trial.

Prior Therapy:

There is no restriction as to the number of prior regimens for metastatic disease as long as patients have adequate performance status. Patients with no prior chemotherapy for metastatic disease and patients who have received prior therapy with taxanes for metastatic disease (taxol or taxotere) are eligible. Stratification will be used for randomization of these two categories (no prior chemotherapy for metastatic disease or prior taxane therapy for metastatic disease).

Chemotherapy treatment prior to enrollment must be discontinued for at least 3 weeks prior to study entry.

Patients must have completed radiation therapy at least 7 days prior to beginning protocol treatment.

Patients must have recovered from all reversible toxicities related to prior therapy before beginning protocol treatment, and may not have any pre- existing treatment-related toxicities in excess of grade 1. Patients must have < grade 2 pre-existing peripheral neuropathy.

Patients may receive bisphosphonates; however, if used, bone lesions may not be used for progression or response.

At least 18 years of age (19 in Alabama).

Life expectancy of greater than 12 weeks.

ECOG performance status < or equal to 2.

Patients must have normal organ and marrow function as defined below:

Absolute neutrophil count: > or equal to 1,500/mcL,

Hemoglobin: > or equal to 9 mg/dL,

Platelets: > or equal to 100,000/mcL,

Total bilirubin: < or equal to 1.5 X institutional upper limit of normal,

Prior use of Abraxane for metastatic disease or in the adjuvant setting.

Metastatic lesions identifiable only by PET.

Patients may not be receiving concurrent chemotherapy for treatment of metastatic disease.

Active brain metastases: evidence of progression < or equal to 3 months after local therapy (patients should be asymptomatic and off corticosteroids and anticonvulsants for at least 3 months prior to study entry).

Patients with brain metastases must have at least one site of measurable disease outside of the central nervous system.

Pregnant or lactating women are excluded. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued if the mother is treated. These potential risks may also apply to other agents used in this study.

A prior invasive malignant disease within five years except for skin cancer (squamous cell or basal cell carcinoma).

Patients with known history of HIV or Hepatitis B because of potential for added toxicity from treatment regimen.

Dementia or altered mental status that would prohibit the understanding of informed consent.

Contacts and Locations

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To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01307891